S171: HIGHER MDMX EXPRESSION WAS ASSOCIATED WITH HYPOMETHYLATING AGENT RESISTANCE AND WORSE SURVIVAL IN MYELODYSPLASTIC SYNDROME PATIENTS, INFERRING IT A POTENTIAL THERAPEUTIC TARGET
Authors: Yu-Hung Wang, Chien-Chin Lin, Chi-Yuan Yao, Kristian Gurashi, Fabio M. R. Amaral, Luciano Nicosia, Bettina Wingelhofer, Kiran Batta, Daniel Wiseman, Hsin-An Hou, Wen Chien Chou, Hwei-Fang Tien
Journal: HemaSphere (2023)

Background: Mutations of TP53 defines a subset of myelodysplastic syndromes (MDS) with resistance to current therapies and rapid progression to AML, emphasizing the crucial role of p53 dysfunction in MDS. The degradation of wild type p53 protein is modulated by the MDM2/MDMX complex. MDMX overexpression has recently been shown to cause the transition of preleukemic stem cells to overt AML in murine models. Meanwhile, the clinical relevance of MDMX expression in MDS patients remains elusive. Aims: This study aims to investigate the clinical and prognostic relevance of MDMX expression in primary MDS patients and to explore the therapeutic potential of MDMX inhibition in concert with hypomethylating agents (HMA) in MDS. Methods: We recruited 340 primary MDS patients treated at the National Taiwan University Hospital from 1997 to 2019 who had adequate BM samples at diagnosis for DNA and RNA sequencing. The diagnoses fit the criteria of the 2022 World Health Organization classification and The International Consensus Classification of Myeloid Neoplasms and Acute Leukemias. We performed cytogenetic study and molecular mutation analysis by targeted next-generation sequencing. Single-sample gene-set enrichment analysis (ssGSEA) was adopted for evaluation of drug resistance. Cell lines were plated in 96 well plates and exposed to the indicated compounds at various concentrations. Cell viability was measured 72h after exposure. Results: The median age of the 340 MDS patients was 68.3 years. Among the 332 patients who had cytogenetic data at diagnosis 4.2%, 25.9%, 23.5%, 22.6% and 23.8% had IPSS-R very-low risk, low risk, intermediate risk, high risk, and very-high risk MDS, respectively. Over a median follow-up of 32.2 months, 161 (47.4%) patients succumbed to the disease, and 106 patients (31%) progressed to AML. High MDMX expression was associated with complex karyotypes and ASXL1 mutations. MDMX expression was significantly higher in MDS patients with excess blasts than those without excess blasts and healthy donors (p<0.001, Figure 1A). Among 290 patients with unmutated TP53, high MDMX patients invariably had significantly poorer overall survival and leukemia-free survival than low MDMX patients (29.1 months vs 91.3 months, p<0.001, and 21.4 months vs 70.3 months, p<0.001, respectively, Figure 1B). Furthermore, time-dependent ROC curve analysis also showed increased area under curve when MDMX expression was incorporated to IPSS-R, indicating its potential to complement IPSS-R, (Figure 1C). In high versus low MDMX patients, the rates of primary resistant to HMA were significantly higher (59.5% vs 22.7%, p<0.001, Figure 1D). Correspondingly, ssGSEA showed that the high MDMX expression group typically expressed higher levels of drug resistance genes (Figure 1E). Last but not least, drugs tests in isogenic cell line model inferred that the combination of MDMX inhibitor with HMA resulted in an additive effect on the killing of THP-1 cells. Conclusion: In summary, we demonstrated that high MDMX expression, in a p53-independent manner, was associated with higher HMA resistance and significantly worse survival in MDS patients. Moreover, drug treatment tests suggested the potential of combinatorial therapy of MDMX inhibitor along with HMA. Further experiments and prospective studies are warranted to support these observations. Figure 1.Keywords: Experimental therapeutics, Hypomethylating agents, MDS, Drug resistance